PMID- 9665189
OWN - NLM
STAT- MEDLINE
DCOM- 19980724
LR  - 20190914
IS  - 0887-6924 (Print)
IS  - 0887-6924 (Linking)
VI  - 12
IP  - 7
DP  - 1998 Jul
TI  - Superiority of high-dose over intermediate-dose cytosine arabinoside in the 
      treatment of patients with high-risk acute myeloid leukemia: results of an 
      age-adjusted prospective randomized comparison.
PG  - 1049-55
AB  - Although cytosine arabinoside (AraC) represents the most effective single agent 
      in the treatment of adults with acute myeloid leukemia (AML) when given at doses 
      exceeding 200 to 500 mg per application, its optimal dosage is still a matter of 
      controversial discussion. While pharmacokinetic investigations suggest that the 
      AraC-activating enzyme deoxycytidine kinase is saturated at drug concentrations 
      achieved by short-term infusion of 0.5 to 1.0 g/m2 AraC and that higher doses are 
      therefore not more effective, recent evidence indicates that additional 
      mechanisms of AraC cytotoxicity may exist which could be enhanced by further dose 
      escalation. In order to test this thesis in the clinical setting, a prospective 
      randomized comparison of high-dose (HD-AraC) vs intermediate-dose (ID-AraC) AraC 
      was carried out in patients with refractory or relapsed AML on the basis of the 
      sequential high-dose AraC and mitoxantrone regimen (S-HAM). AraC was given as a 
      3-h infusion q 12 h on days 1, 2, 8 and 9. Patients younger than 60 years were 
      randomized to AraC doses of 3.0 g/m2 vs 1.0 g/m2 while older patients received 
      either 1.0 g/m2 or 0.5 g/m2 per single dose. Mitoxantrone was given to all 
      patients on days 3, 4, 10 and 11 at a daily dose of 10 mg/m2. Randomization was 
      stratified for primary refractoriness against induction therapy and length of 
      first remission in relapsed patients. From 186 evaluable patients, 88 (47%) and 
      10 cases (5%) achieved a complete (CR) or partial (PR) remission, 39 patients 
      (21%) had persisting leukemia (non-response (NR)), and 49 cases (26%) died within 
      6 weeks after the start of therapy (early death (ED)). In patients younger than 
      60 years the higher dose level resulted in a significant reduction of NR (12% vs 
      31%; ordinal chi2 test: P = 0.01) but also a higher rate of ED (32% vs 17%) thus 
      leading to a marginally higher CR rate only (52% vs 45%). Within the subgroup of 
      patients with refractory AML the tendency towards a higher CR rate after HD-AraC 
      was more pronounced (46% vs 26%; P = 0.045). In patients older than 60 years, 
      corresponding though less evident differences were observed with a higher rate of 
      NR in the lower dose group (26% vs 16%) and ED occurring more frequently after 
      higher doses (36% vs 26%). These data indicate that HD-AraC reveals a 
      significantly higher antileukemic efficacy than ID-AraC as expressed by a 
      significant reduction of failure from NR. This advantage, however, does not fully 
      translate into an increase in remission rate due to a higher incidence of ED 
      after HD-AraC predominantly from uncontrolled infections. In order to take full 
      advantage of the higher antileukemic activity of HD-AraC an improvement of 
      supportive care and infection control is warranted.
FAU - Kern, W
AU  - Kern W
AD  - Department of Hematology and Oncology, University of Gottingen, Germany.
FAU - Aul, C
AU  - Aul C
FAU - Maschmeyer, G
AU  - Maschmeyer G
FAU - Schonrock-Nabulsi, R
AU  - Schonrock-Nabulsi R
FAU - Ludwig, W D
AU  - Ludwig WD
FAU - Bartholomaus, A
AU  - Bartholomaus A
FAU - Bettelheim, P
AU  - Bettelheim P
FAU - Wormann, B
AU  - Wormann B
FAU - Buchner, T
AU  - Buchner T
FAU - Hiddemann, W
AU  - Hiddemann W
LA  - eng
PT  - Clinical Trial
PT  - Comparative Study
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
PL  - England
TA  - Leukemia
JT  - Leukemia
JID - 8704895
RN  - 04079A1RDZ (Cytarabine)
RN  - BZ114NVM5P (Mitoxantrone)
RN  - NOAC protocol
SB  - IM
MH  - Acute Disease
MH  - Adolescent
MH  - Adult
MH  - Age Factors
MH  - Aged
MH  - Antineoplastic Combined Chemotherapy Protocols/adverse effects/*therapeutic use
MH  - Cytarabine/administration & dosage
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Humans
MH  - Leukemia, Myeloid/*drug therapy
MH  - Male
MH  - Middle Aged
MH  - Mitoxantrone/administration & dosage
MH  - Prospective Studies
MH  - Risk Factors
EDAT- 1998/07/17 00:00
MHDA- 1998/07/17 00:01
CRDT- 1998/07/17 00:00
PHST- 1998/07/17 00:00 [pubmed]
PHST- 1998/07/17 00:01 [medline]
PHST- 1998/07/17 00:00 [entrez]
AID - 10.1038/sj.leu.2401066 [doi]
PST - ppublish
SO  - Leukemia. 1998 Jul;12(7):1049-55. doi: 10.1038/sj.leu.2401066.